The invention relates to the field of treatment of neurological and psychological disorders.
Investigations which utilize functional magnetic resonance imaging (fMRI) techniques have begun to map the regions of the brain that are active during learning, memory, and emotional experiences. Of these regions, the amygdala and, the prefrontal cortex have been shown to be particularly important in affective experience and its modulation. The amygdala has consistently emerged as one of the most critical for ascribing emotional significance to stimuli and influencing affective responsiveness and emotional learning (LeDoux, 1996; Davis, 1997). Neuroimaging studies of adults have shown that the amygdala often produces increased activation in response to several types of affective stimuli, and is activated consistently during the perception of fearful facial expressions (Breiter and Rauch, 1996; Morris et al., 1996; Phillips et al., 1997; Baird et al., 1999). fMRI investigations of individuals with affective disorders, schizophrenia (Kosaka et al., 2002), and autism (Baron-Cohen et al., 1999) have shown an abnormal activation of the amygdala in response to facial emotions and other social stimuli.
Neuroimaging research has also shown that the same amygdala regions that are responsive to the affective value of visual stimuli are also sensitive to pharmacologic manipulation. For example, Kalin and colleagues (1997) demonstrated that while viewing positively and negatively valenced stimuli, depressed patients, unlike control subjects, displayed no amygdalar activation in response to positive stimuli during a baseline evaluation (Kalin et al., 1997). However, following treatment with venlafaxine, depressed patients showed a significant increase in activation to the same positive stimuli. In a study by Sheline and colleagues, depressed patients initially showed increased activation in the left amygdala compared to control subjects when viewing masked emotional faces. Following treatment, the depressed patients exhibited decreased activation in the left amygdala compared to baseline, whereas, control subjects demonstrated no difference in activation between the initial and follow up scans (Sheline et al., 2001). In an additional recent study using negatively and positively valenced words as stimuli, Siegle et al. reported that amygdalar activation to negative words in depressed patients extended significantly longer than the activation produced by control subjects (Siegle et al., 2002). Moreover, a recent study by Hariri et al. (2002) reported increased amygdalar responsivity to facial affect in healthy subjects following the administration of dextroamphetamine, a dopaminergic psychostimulant. The authors suggested that this augmentation may be due to either dopamine-mediated enhancement of excitatory input to the amygdala or attenuation of inhibitory prefrontal input (Hariri et al., 2002).
Abnormal amygdalar function is implicated in many disorders, such as bipolar disorder, that are often recalcitrant to treatment or require treatments that have significant side effects. By focusing on normalizing amygdalar function, it may be possible to treat a variety of conditions with only one therapeutic agent or combination of therapeutic agents. Accordingly, there is a need for novel therapeutic agents to treat disorders associated with the amygdala.